Topical pharmaceutical composition of acitretin

ABSTRACT

The present invention relates to a topical pharmaceutical composition comprising acitretin and a process for its preparation. It also relates to a method of treating skin disorders by administering said topical pharmaceutical composition.

FIELD OF THE INVENTION

The present invention relates to a topical pharmaceutical compositioncomprising acitretin and a process for its preparation. It also relatesto a method of treating skin disorders by administering said topicalpharmaceutical composition.

BACKGROUND OF THE INVENTION

Psoriasis is a chronic, non-contagious skin disorder. It appears in manydifferent forms and can affect any part of the body.

Currently, there is no cure for psoriasis. However, over the years awide variety of topical and systemic treatment methods that inhibit theinflammation, cell proliferation, or cell differentiation have beendeveloped. Treatment of psoriasis remains a challenge because of itschronic recurrent nature. Various topical and systemic therapies includeanti-inflammatory agents, e.g., glucocorticoids; analgesics; chemicallysynthesized disease-modifying antirheumatic drugs (DMARDs), e.g.,methotrexate and ciclosporin; antiproliferative agents, e.g., retinoidsand vitamin D analogs; TNF-a blockers, e.g., etanercept, infliximab,adalimumab, and efalizumab; monoclonal antibodies against B cells, e.g.,rituximab; T-cell activation blockers, e.g., abatacept; IL-1 blockers,e.g., anakinra; coal tar; and phototherapy.

These treatment methods have proven to be of limited value due todisadvantages such as cosmetic liabilities, severe side effects, highcost, and minimal or short-term efficacy.

Retinoids, as an alternative, are also known to influence keratinocytedifferentiation and have proven to be effective in the treatment of avariety of keratinization disorders including psoriasis.

U.S. Pat. No. 6,353,029 discloses a topical solution compositioncomprising tretinoin, 4-hydroxy anisole, polyethylene glycol, anantioxidant, a chelating agent, a lower alkanol, and water.

U.S. Pat. No. 5,643,584 discloses a topical aqueous gel compositioncomprising unsolubilized micronized tretinoin particles, a surfactantselected from the group consisting of octoxynol and nonoxynol, apreservative, a gelling agent, and water. PCT Publication No. WO90/14833 discloses an aqueous gel vehicle for topical application to theskin comprising active ingredients such as retinoids, in particulartretinoin. The composition also includes an aqueous medium, a gellingagent, and an antioxidant.

U.S. Pat. Nos. 5,914,334 and 6,258,830 disclose topical gel compositionsof tazarotene comprising poloxamer 407, polysorbate 40, and hexyleneglycol for the treatment of acne and psoriasis.

A review of the prior art thus reveals topical pharmaceuticalcompositions of retinoids such as tretinoin and tazarotene for thetreatment of skin disorders such as psoriasis. However, irritancy to theskin remains the common side effect, leading to a high level of patientnon-compliance.

Acitretin, a metabolite of etretinate, is available as an oral capsuledosage form and is indicated for the treatment of severe psoriasis. Asthe use of acitretin is limited by its systemic side effects, and skinbeing the target organ for the treatment of psoriasis, there remains anunmet need for topical pharmaceutical compositions of acitretin withminimal or no systemic side effects and with reduced irritancy to theskin.

For a topical pharmaceutical composition, the solubilization and releaseof a drug from the composition remain the essential prerequisites toensure effective treatment. As acitretin is poorly soluble in water, itremains a great challenge to develop a topical pharmaceuticalcomposition in which acitretin is maximally solubilized and readilyreleased from the composition into the skin.

The scientists of the present invention have now developed a topicalpharmaceutical composition of acitretin with an acceptable level ofefficacy for treating psoriasis and with reduced irritancy. Further,acitretin is found to be readily released from the composition into theskin. Also, said composition of the present invention is found to bestable.

SUMMARY OF THE INVENTION

The topical pharmaceutical composition of the present invention is asignificant advance over the currently available oral dosage form ofacitretin, as there are minimal or no systemic side effects. Further,the topical pharmaceutical composition of acitretin results in betterpatient compliance in comparison to the available oral dosage form. Inparticular, the topical pharmaceutical composition of acitretin is inthe form of a gel and is found to be stable for at least three months.

The present invention relates to a topical pharmaceutical compositioncomprising acitretin and a process for its preparation. It also relatesto a method of treating a skin disorder by administering said topicalpharmaceutical composition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a bar chart presentation of mean utriculi size afterapplication of various strengths of acitretin gels and Tazorac®(tazarotene)

FIG. 2 is a bar chart presentation of percentage reduction in utriculisize after application of various strengths of acitretin gels andTazorac® (tazarotene) gel with respect to control.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the present invention provides a stable topicalpharmaceutical composition of acitretin comprising a therapeuticallyeffective amount of acitretin and one or more gelling agents.

According to one embodiment of this aspect, the percentage of gellingagent ranges from about 0.05% w/w to about 10% w/w of the composition.

According to another embodiment of this aspect, the gelling agent is acarboxyvinyl polymer.

According to another embodiment of this aspect, the topicalpharmaceutical composition consists essentially of acitretin as theactive ingredient, one or more gelling agents to form a gel, a solventin which to disperse the gelling agent, and a co-solvent in which todissolve the acitretin. Combining the one or more gelling agents andsolvent for dispersing the gelling agent with the solution ofacitretin/co-solvent provides a gel of acitretin suitable for topicaladministration.

The topical pharmaceutical composition may consist essentially of one ormore gelling agents being present at a percentage ranging from about0.05% w/w to about 10% w/w based on the total weight of the composition,one or more solvents to disperse the one or more gelling agents, theacitretin present in an amount of about 0.02% w/w to about 5% w/w basedon the total weight of the composition, and one or more co- solvents todissolve the acitretin,

According to another embodiment of this aspect, the topicalpharmaceutical composition consists of acitretin as the sole activeingredient, one or more gelling agents to form a gel, a solvent in whichto disperse the gelling agent, and a co-solvent in which to dissolve theacitretin. Combining the one or more gelling agents and solvent fordispersing the gelling agent with the solution of acitretin/co-solventprovides a gel of acitretin suitable for topical administration,

In one embodiment, the topical pharmaceutical compositions disclosedherein are characterized as being unencapsulated.

A second aspect of the present invention provides a stable topicalpharmaceutical composition comprising more than about 0.05% w/wofacitretin, wherein the composition has a mean in-vitro release rate ofmore than about 10.00 μg/cm²/h^(1/2) as measured using a Franz diffusioncell with the conditions of receptor solution comprising isopropylalcohol and water (60:40, v/v), the membrane a Supor® 200, dosage 300±30mg, temperature 32° C.±1.0° C.

A third aspect of the present invention provides a process for thepreparation of a stable topical pharmaceutical composition of acitretin,wherein the process comprises the steps of:

-   -   (i) dispersing one or more gelling agents in a suitable solvent;    -   (ii) dispersing/dissolving acitretin and one or more        pharmaceutically acceptable excipients in a suitable co-solvent;        and    -   (iii) mixing the dispersion of step (i) with the        dispersion/solution of step (ii) to form a gel.

A fourth aspect of the present invention provides a method of treating askin disorder by administering a stable topical pharmaceuticalcomposition of acitretin comprising a therapeutically effective amountof acitretin and one or more gelling agents.

According to one embodiment of this aspect, the skin disorder isselected from the group comprising psoriasis, keratosis, eczema,rosacea, acne vulgaris, dermatitis, pruritus, seborrhea, skin cancers,inflammation, other skin disorders which ate responsive to acitretin oretretinate, and combinations thereof.

According to another embodiment of this aspect, the skin disorder ispsoriasis.

According to another embodiment of this aspect, the skin disorder iskeratosis.

The term “topical,” as used herein, refers to a composition meant forapplication to the skin, nail, or mucosal tissue.

The term “therapeutically effective amount,” as used herein, refers toan amount effective at dosages and for periods of time necessary toachieve the desired result of treating skin disorders, in particularpsoriasis and keratosis.

The term “pharmaceutical composition,” as used herein, refers to gels,solutions, suspensions, foams, lotions, or sprays. In particular, thepharmaceutical composition of the present invention is a gel.

The term “acitretin,” as used herein, refers toall-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoicacid. It further includes its salts, polymorphs, hydrates, solvates,prodrugs, chelates, or complexes. The topical pharmaceutical compositionof the present invention comprises acitretin in an amount from about0.005% w/w to about 10% w/w, in particular from about 0.02% w/w to about5% w/w based on total weight of the composition.

The term “about,” as used herein, refers to any value which lies withinthe range defined by a variation of up to ±10% of the value.

The term “stable,” as used herein, means not more than 10% w/w of totalrelated substances are formed on storage at a temperature of 40° C. anda relative humidity of 75% or at a temperature of 25° C. and a relativehumidity of 60%, for a period of at least three months to the extentnecessary for the sale and use of the composition without substantialchange in the mean in-vitro release rate of acitretin from thecomposition. The mean in- vitro release rate of acitretin from thetopical pharmaceutical compositions of the present invention uponstorage at 40° C./75% relative humidity (RH) for at least three monthsis substantially similar to the initial mean in-vitro release rate ofacitretin obtained as soon as practicable after preparation of topicalpharmaceutical compositions.

The term “substantial,” as used herein, refers to any value which lieswithin the range defined by a variation of up to ±20% of the value.

The term “gelling agent,” as used herein, refers to an agent which formsa gel when added to a suitable solvent. Suitable gelling agents areselected from the group comprising carboxyvinyl polymers, e.g., Carbopol980, Carbopol 974P, Carbopol 971P, and Carbopol® 934P; natural gums,e.g., karaya gum, locust bean gum, guar gum, xanthan gum, arabic gum,tragacanth gum, carrageenan, pectin, agar, alginic acid, and sodiumalginate; cellulose derivatives, e.g., hydroxypropyl methyl cellulose,hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, andsodium carboxymethylcellulose;

acrylates, e.g., methacrylates and polyacrylates; alginic acid-propyleneglycol esters; polyoxyethylene-polyoxypropylene copolymers; polyvinylpyrrolidone; polyethylene glycol; polyethylene oxide; polyvinyl alcohol;silicon dioxide; and mixtures thereof. In particular, the gelling agentused in the topical pharmaceutical composition of the present inventionis a carboxyvinyl polymer. The topical pharmaceutical composition of thepresent invention comprises a gelling agent in an amount of from about0.05% w/w to about 10% w/w, in particular from about 0.1% w/w to about5% w/w, based on total weight of the composition.

Acitretin being poorly insoluble in water, a plurality of non-aqueousvehicles as co-solvents has been used in the present invention tosolubilize acitretin. The term “co-solvent,” as used herein, refers toan organic solvent which is used to disperse or dissolve acitretin.Suitable co-solvents are selected from the group comprising ethers,e.g., diethylene glycol monoethyl ether; glycols, e.g., propyleneglycol, polyethylene glycol, and glycerin; dimethyl isosorbide; fattyacid esters, e.g., isopropyl myristate, isopropyl palmitate, isopropylstearate, and ethyl oleate; fatty acids, e.g., capric acid, lauric acid,myristic acid, oleic acid, and linoleic acid; polyoxyethylene sorbitanesters, e.g., polysorbate 20, polysorbate 40, polysorbate 60, andpolysorbate 80; and mixtures thereof. Certain water-miscible solvents,e.g., glycerin or propylene glycol, also add beneficial humectantproperties to the composition. The amount of co-solvent used in thepresent invention ranges from about 15% w/w to about 45% w/w, morepreferably from about 20% w/w to about 30% w/w based on the total weightof the composition. In the present invention, the total amount ofacitretin may be present as solubilized acitretin fraction and remainingas unsolubilized acitretin fraction.

The selection of co-solvents remains an important factor as itdetermines the solubility and release of acitretin from the composition.In a preferred embodiment, the co-solvent is a combination of diethyleneglycol monoethyl ether present in a range of about 20% w/w to about 30%w/w, dimethyl isosorbide present in a range of about 1% w/w to about 10%w/w, and polysorbate 80 present in a range of about 0.1% w/w to about 5%w/w, based on total weight of the composition. The solubility ofacitretin increases to approximately 10,000 times in comparison tosolubility in water, when dimethyl isosorbide, diethylene glycolmonoethyl ether, and polysorbate 80 are used in a w/w ratio of about3.3:24.1:1. Besides increasing the solubility to a remarkable level, thecombination of these co-solvents also helps to provide the desirablerelease of acitretin from the composition into the skin.

The term “solvent,” as used herein, refers to a vehicle used to disperseor dissolve one or more gelling agents. Suitable solvents are selectedfrom the group comprising water, white soft paraffin, light liquidparaffin, heavy liquid paraffin, mineral oil, hydrocarbon oil, esteroil, triglyceride oil, oil of plant origin, oil of animal origin,unsaturated or polyunsaturated oil, essential oil, silicone oil, andmixtures thereof, In particular, the solvent used in the topicalpharmaceutical composition of the present invention is water.

The topical pharmaceutical composition of the present invention furthercomprises one or more pharmaceutically acceptable excipients selectedfrom the group comprising percutaneous absorption enhancers,antioxidants, preservatives, chelating agents, surfactants, pH-adjustingagents, humectants, fragrances, and mixtures thereof.

Suitable percutaneous absorption enhancers are selected from the groupcomprising sulfoxides, e.g., dimethyl sulfoxide (DMSO); ethers, e.g.,diethylene glycol monoethyl ether (Transcutol®); surfactants, e.g.,sodium laurate, sodium lauryl sulfate, polysorbate 20, polysorbate 40,polysorbate 60, and polysorbate 80; alkyl glycosides; alcohols, e.g,,ethanol, propanol, and benzyl alcohol; fatty acids, e.g., lauric acid,oleic acid, valeric acid, and isostearic acid; fatty acid esters, e.g.,isopropyl myristate and isopropyl palmitate; polyols or esters thereof,e.g., propylene glycol, ethylene glycol, glycerol, butanediol, andpolyethylene glycol; amides or other nitrogenous compounds, e.g., urea,dimethyl acetamide, dimethyl formamide, 2-pyrrolidone,1-methyl-2-pyrrolidone, ethanolamine, diethanolamine, andtriethanolamine; terpenes; dimethyl isosorbide; alkanones; and mixturesthereof.

Suitable antioxidants are selected from the group comprising butylatedhydroxy anisole, butylated hydroxy toluene, sodium metabisulfite,ascorbic acid, ascorbyl palmitate, thiourea, acetylcysteine,dithiothreitol, cysteine hydrochloride, propyl gallate, tent-butylhydroquinone, beta-carotene, tocopherols, and mixtures thereof.

Suitable preservatives are selected from the group comprising methyl-,ethyl-, propyl-, or butyl-esters of hydroxy benzoic acid or sodium saltsthereof, benzoic acid, sodium benzoate, chlorhexedine, benzalkoniumchloride, 2-phenoxyethanol, cetrimide, potassium sorbate, imidurea,dichlorobenzyl alcohol, thiomersal, and mixtures thereof.

Suitable chelating agents are selected from the group comprisingethylenediamine tetraacetic acid or derivatives or salts thereof, e.g.,disodium edetate; dihydroxyethyl glycine; glucamine; acids, e.g., citricacid, tartaric acid, gluconic acid, and phosphoric acid; and mixturesthereof.

Suitable surfactants are selected from the group comprisingpolyethoxylated fatty acid esters, polyoxyethylene sorbitan esters,polyoxyethylene hydrogenated castor oil, polyoxyethylenepolyoxypropylene glycol, sorbitan esters, sodium lauryl sulphate,docusate sodium, nonooxynol, glyceryl monostearate, and mixturesthereof.

Suitable pH-adjusting agents are selected from the group comprisingorganic or inorganic acids, e.g., citric acid, acetic acid, fumaricacid, tartaric acid, phosphoric acid, and hydrochloric acid; organic orinorganic bases, e.g., sodium hydroxide, potassium hydroxide, ammoniumhydroxide, and triethanolamine; and buffers, e.g., phosphate buffers andacetate buffers. The pH of the topical pharmaceutical composition of thepresent invention is adjusted from about 4 to about 7.

Suitable humectants are selected from the group comprising propyleneglycol, glycerin, butylene glycol, sorbitol, triacetin, and mixturesthereof.

Examples of fragrances that may be used in the composition includelavender oil, rose oil, lemon oil, almond oil, other FDA-approvedfragrances, and mixtures thereof.

The compositions of the present invention may further comprise anauxiliary agent, which may act as a cooling agent. Suitable coolingagents are selected from the group comprising menthol, e.g., l-mentholand dl-menthol; camphor, e.g., d-camphor and dl- camphor; borneol, e.g.,d-borneol and dl-borneol; and mixtures thereof. Plant oils and extractscontaining one or more of these compounds, e.g., peppermint oil,peppermint extract, camphor tree extract, and lavender extract, may alsobe used.

The following examples represent various embodiments according to thepresent invention. The examples are given solely for the purpose ofillustration and are not to be construed as limitations of the presentinvention, as many variations thereof are possible without departingfrom the spirit and scope of the invention.

EXAMPLES Example 1

Ingredients Quantity (% w/w) Acitretin 0.20 Diethylene glycol monoethylether 24.20 Dimethyl isosorbide 3.33 Butylated hydroxy anisole 0.05Carbopol ® 980 0.50 Sodium hydroxide solution q.s. Purified water q.s.to 100.00

Procedure:

-   -   1. Carbopol 980 was dispersed in purified water under stirring.    -   2. Acitretin, butylated hydroxy anisole, and dimethyl isosorbide        were added into diethylene glycol monoethyl ether and mixed        together.    -   3. The mixture of step 2 was added into the dispersion of step 1        under stirring.    -   4. Purified water was added into the dispersion of step 3 to        achieve the desired weight.    -   5. The pH of the dispersion of step 4 was adjusted to 5 to 6        using sodium hydroxide solution to form a gel.

Example 2

Ingredients Quantity (% w/w) Acitretin 0.20 Diethylene glycol monoethylether 24.10 Dimethyl isosorbide 3.30 Polysorbate 80 1.00 Ascorbic acid0.05 Butylated hydroxy anisole 0.05 Disodium edetate 0.10 Sodiumbenzoate 0.20 Carbopol ® 980 1.25 Sodium hydroxide solution q.s.Purified water q.s. to 100.00

Procedure:

-   -   1. Carbopol 980 was dispersed in purified water under stirring.    -   2. Acitretin, butylated hydroxy anisole, dimethyl isosorbide,        and polysorbate 80 were added into diethylene glycol monoethyl        ether and mixed together.    -   3. Disodium edetate, sodium benzoate, and ascorbic acid were        dissolved into purified water.    -   4. The mixture of step 2 was added into the dispersion of step        1.    -   5. The mixture of step 3 was added into the dispersion of step        4.    -   6. Purified water was added into the dispersion of step 5 to        achieve the desired weight.    -   7. The pH of the dispersion of step 6 was adjusted to 5 to 6        using sodium hydroxide solution to form a gel.

Examples 3-7

Quantity (% w/w) Exam- Exam- Exam- Exam- Exam- Ingredients ple 3 ple 4ple 5 ple 6 ple 7 Acitretin 0.02 0.05 0.10 0.15 0.25 Diethylene glycol24.10 24.10 24.10 24.10 24.10 monoethyl ether Dimethyl isosorbide 3.303.30 3.30 3.30 3.30 Polysorbate 80 1.00 1.00 1.00 1.00 1.00 Butylatedhydroxy 0.05 0.05 0.05 0.05 0.05 anisole Carbopol ® 980 1.25 1.25 1.251.25 1.25 Disodium edetate 0.10 0.10 0.10 0.10 0.10 Sodium benzoate 0.200.20 0.20 0.20 0.20 Ascorbic acid 0.05 0.05 0.05 0.05 0.05 Sodiumhydroxide q.s. q.s. q.s. q.s. q.s. solution Purified water q.s. to q.s.to q.s. to q.s. to q.s. to 100.00 100.00 100.00 100.00 100.00

Examples 8-13

Quantity (% w/w) Example Example Example Example Ingredients Example 8Example 9 10 11 12 13 Acitretin 0.30 0.40 1.00 0.02 0.05 0.10 Diethylene24.10 24.10 24.10 24.28 24.25 24.20 glycol monoethyl ether Dimethyl 3.303.30 3.30 3.30 3.30 3.30 isosorbide Polysorbate 80 1.00 1.00 1.00 1.001.00 1.00 Butylated 0.05 0.05 0.05 0.05 0.05 0.05 hydroxy anisoleCarbopol ® 980 1.25 1.25 1.25 1.25 1.25 1.25 Disodium 0.10 0.10 0.100.10 0.10 0.10 edetate Sodium 0.20 0.20 0.20 0.20 0.20 0.20 benzoateAscorbic acid 0.05 0.05 0.05 0.05 0.05 0.05 Sodium q.s. q.s. q.s. q.s.q.s. q.s. hydroxide solution Purified water q.s. to 100.00 q.s. to100.00 q.s. to 100.00 q.s. to 100.00 q.s. to 100.00 q.s. to 100.00

Procedure:

-   -   1. Carbopol 980 was dispersed in purified water under stirring.    -   2. Acitretin, butylated hydroxy anisole, dimethyl isosorbide,        and polysorbate 80 were added into diethylene glycol monoethyl        ether and mixed together.    -   3. Disodium edetate, sodium benzoate, and ascorbic acid were        dissolved into purified water.    -   4. The mixture of step 2 was added into the dispersion of step        1.    -   5. The mixture of step 3 was added into the dispersion of step        4.    -   6. Purified water was added into the dispersion of step 5 to        achieve the desired weight.    -   5. The pH of the dispersion of step 6 was adjusted to 5 to 6        using sodium hydroxide solution to form a gel.

Solubility Studies

The saturation solubility of acitretin was determined by adding anexcess amount of acitretin in a conical flask containing a mixture ofdimethyl isosorbide, diethylene glycol monoethyl ether, and polysorbate80, present in a w/w ratio of 3.3:24.1:1. The mixture was kept in ashaking water bath for 24 hours at 25° C. The saturation solubility ofacitretin was measured to be 2.5 mg/mL by HPLC method [YIN/IC-Pack®ODS-A column C-18 (150×4.6 mm, 5 μm); mobile phase ofmethanol:ethanol:glacial acetic acid:water (74:21:5:0.5 v/v/v/v); flowrate of 1.5 mL/min; UV detection at 360 nm].

The solubility of acitretin was found to be 0.7025 mg/g of the gel ingiven compositions of Examples 5 through 10 containing 0.284 g of amixture of dimethyl isosorbide, diethylene glycol monoethyl ether, andpolysorbate 80, present in a w/w ratio of 3.3:24.1:1. Table 1 gives thepercentage of the acitretin in a solubilized form in acitretin gelsprepared as per Examples 2 through 9.

TABLE 1 Percentage of Acitretin Solubilized in Acitretin Gels Preparedas per Examples 2-9 Example Percentage of Acitretin Solubilized 2 35.133 100.00 4 100.00 5 70.25 6 46.83 7 28.10 8 23.42 9 17.56

Stability Data

The gels prepared according to Example 1, Example 2, Example 11, Example12, and Example 13 were stored at a temperature of 40° C. and a relativehumidity of 75% RH for a period of three to six months, and analyzed foracitretin contents by HPLC method [YMC-Pack® ODS-A column C-18 (150×4.6mm, 5 μm); mobile phase of methanol:ethanol:glacial acetic acid:water(74:21:5:0.5 v/v/v/v); flow rate of 1.5 mL/min; UV detection at 360 nm].The results of the analysis are represented in Tables 2-4.

TABLE 2 Results of the Stability Study of the Gel Prepared According toExample 1 Conditions Related Substances (40° C./75% RH) Assay (%) (%w/w) Initial 101.2 0.14 3 Months 102.6 0.13

TABLE 3 Results of the Stability Study of the Gel Prepared According toExample 2 Conditions Related Substances (40° C./75% RH) Assay (%) (%w/w) Initial 96.6 0.17 3 Months 100.0 0.18 6 Months 100.5 0.44

TABLE 4 Results of the Stability Study of the Gel Prepared According toExamples 11-13 Conditions Related substances Example (40° C./75% RH)Assay (%) (% w/w) 11 Initial 101.9 0.54 3 Months 103.8 0.64 6 Months103.7 1.03 12 Initial 97.3 0.23 3 Months 100.0 0.32 6 Months 101.7 0.7313 Initial 97.3 0.19 3 Months 98.7 0.20 6 Months 101.4 0.48

In-Vitro Release Data

An in-vitro release test was performed using a Franz diffusion cellhaving six individual cells and a Supor® 200 membrane. The receptorsolution used was isopropyl alcohol and water (60:40, v/v). 300 Mg ofthe gels prepared according to Examples 2 and 5-9 were placed uniformlyon the membrane at a temperature of 32° C.±1.0° C. The amount ofacitretin released was determined using an HPLC method [Zorbax® columnC-18 (150×4.6 mm, 5 μm); mobile phase of buffer:methanol (10:90 v/v);buffer of 20 mM ammonium acetate:acetic acid (1000:30 v/v); flow rate of0.750 mL/min] and was analyzed using a UV detector at 350 nm. The meanacitretin release rate at 0 days, 3 months, and 6 months at 40° C/75% RHfrom gels prepared as per Example 2 and 5-9 is given in Table 5.

TABLE 5 Mean In-vitro Release Rate of Acitretin Gels Prepared as perExamples 2 and 5-9 Mean Release Rate (μg/cm²/h^(1/2)) 3 Months 6 MonthsExample Initial (Control) (40° C./75% RH) (40° C./75% RH) 2 26.16 25.8724.90 5 15.90 17.26 15.66 6 19.28 15.94 15.92 7 19.87 15.94 18.70 823.04 21.50 20.35 9 28.51 25.01 24.24

From the above table, it is clear that the mean in-vitro release rate ofacitretin upon storage at 40° C./75% RH after 6 months is substantiallysimilar to the initial mean in-vitro release rate from the controlbatches.

Rhino Mouse Test Efficacy Studies

Rhino mouse utriculi reduction assay is a well-characterized animalmodel for the evaluation of retinoid activity (Kligman and Kligman, “TheEffect on Rhino Mouse Skin of Agents which Influence Keratinization andExfoliation,” J. Invest. Dermatol., 73(5pI):354-358, 1979) Rhino mouseskin is characterized by the presence of keratin-containing utriclesattached to the epidermis. The utricle size reduction in rhino mouse canbe used to determine the efficacy of a composition for the treatment ofpsoriasis (Hsia et al., “Effects of Topically Applied Acitretin inReconstructed Human Epidermis and the Rhino Mouse,” J. Invest.Dermatol., 128(1):125-130, 2008). Acitretin gels of the presentinvention are compared with commercially available Tazorac® (tazarotene)gel 0.10% w/w indicated for the treatment of psoriasis.

Seven groups were made, each consisting of seven animals as described inTable 6. An amount of 100 mg±2% of placebo for acitretin gel, acitretingels of various strengths, and reference Tazorac® (tazarotene) gel 0.10%w/w was applied evenly on the entire dorsal trunk of the animals with asterilized spatula/glass rod daily for 14 consecutive days. All theanimals from Group Ito Group VII were examined for detailed clinicalsigns once daily during treatment and during the treatment-free period.

TABLE 6 Study Design for Acitretin Gel for Rhino Mouse TestFormulation/Treatment Concentration Animal Numbers & Groups Details (%w/w) Sex I Control — 1-7 (5 males, 2 females) II Placebo for acitretingel — 8-14 (4 males, 3 females) III Acitretin gel 0.02 15-21 (Example 3)(4 males, 3 females) IV Acitretin gel 0.05 22-28 (Example 4) (4 males, 3females) V Acitretin gel 0.10 29-35 (Example 5) (4 males, 3 females) VIAcitretin gel 0.20 36-42 (Example 2) (4 males, 3 females) VII Tazorac ®(tazarotene) 0.10 43-49 gel (4 males, 3 females)

After about 72±3 hours following last application (i.e., day 14), allsurviving animals were euthanized by cervical dislocation and skintissue samples (ventral side skin—untreated control site and dorsal sideskin - application site) were collected and preserved in 10% neutralbuffered formalin for histopathology evaluation. In addition to this,some portion of the dorsal side skin (i.e. , application site) from allthe animals was also collected in a 0.5% v/v acetic acid solution forwhole mount slide preparations and measurement of utriculi diameter.

For whole mount preparations, the skin samples (dorsal side skin, i.e.,application site) were cut into approximately 1×1 cm² size and soaked in0.5% v/v acetic acid solution for approximately 18±1 hours at atemperature of 2° C. to 8° C. The epidermis was carefully peeled offusing a flat-ended spatula/blade/fine forceps and placed on a glassslide with the dermal side facing up, and the slides were allowed toair-dry. These tissue slides were later dehydrated by immersing intoascending grades of isopropyl alcohol (75%, 95%, and 100% forapproximately 3 minutes to 5 minutes each), followed by xylene, and thenmounted. The diameter of at least 10 utriculi (2 utriculi/field) wasmeasured by using a Leica® Application Suite QWin Image Processing andAnalysis Software. Mean utricle diameter was calculated for each animaland subjected for group mean comparison by using one way analysis ofvariance (ANOVA) if complied normality test using D'Agostino-Pearsonomnibus. As ANOVA results showed significance, a Dunnett test wasapplied to compare Group II to Group VII with/over untreated control(Group I) and Group III to Group VII with/over placebo (Group II).

The percentage reduction in utriculi diameter was calculated manuallybased on mean reduction in the utriculi diameter in different groupswith respect to the untreated control (Group I) and placebo (Group II)by using the following formula.

${{Percentage}\mspace{14mu} {Reduction}\mspace{14mu} {in}\mspace{14mu} {utricle}\mspace{14mu} {diameter}} = {\frac{\begin{matrix}{{{Mean}\mspace{14mu} {Utricle}\mspace{14mu} {Diameter}\mspace{14mu} {in}\mspace{14mu} {Untreated}\mspace{14mu} {Control}\mspace{14mu} {or}\mspace{14mu} {Placebo}} -} \\{{Mean}\mspace{14mu} {Utricle}\mspace{14mu} {Diameter}\mspace{14mu} {in}\mspace{14mu} {Group}\mspace{14mu} X}\end{matrix}}{{Mean}\mspace{14mu} {Utricle}\mspace{14mu} {Diameter}\mspace{14mu} {in}\mspace{14mu} {Untreated}\mspace{14mu} {Control}\mspace{14mu} {or}\mspace{14mu} {Placebo}} \times 100}$

wherein “X” is the group for which percentage reduction in utriclediameter was calculated.

Table 7 describes the summary of utriculi size/diameter afterapplication of various strengths of acitretin gels and Tazorac®(tazarotene) gel 0.10% w/w. In the untreated control (Group I) andplacebo (Group II) animals, numerous circular-shaped utriculi werenoticed in the epidermal sheets (whole mount preparation) with anaverage diameter of 255.38±37.16 and 233.61±35.41 μm. Application ofacitretin gel at all concentrations (0.02% w/w, 0.05% w/w, 0.10% w/w,and 0.20% w/w) produced a significant reduction in the utriculi diameterwith an average diameter of 109.52±57.56, 60.30±6.46, 63.64±5.19 and57.46±5.65 μm in Group III, Group IV, Group V, and Group VI,respectively. Similarly, in Group VII (Tazorac® gel 0.10% w/w), the meanutriculi diameter was reduced up to 45.48±7.33 μm. FIG. 1 shows the meanutriculi size after the application of various strengths of acitretingel and Tazorac® (tazarotene) gel 0.10% w/w. FIG. 2 shows the percentagereduction in utriculi size after the application of various strengths ofacitretin gel and Tazorac® (tazarotene) gel 0.10% w/w with respect tocontrol.

TABLE 7 Summary of Utriculi Size/Diameter Group I II III IV V VI VIIMean 255.38 ± 37.16 233.61 ± 35.41 109.52**@@ ± 57.56 60.30**@@ ± 6.4663.64**@@ ± 5.19 57.46**@@ ± 45.48**@@ ± Diameter/Size 5.65 7.33 (inmicrons) ± SD N 7 7 7 7 7 7 7 % Reduction 0 8.53 57.12 76.39 75.08 77.5082.19 with respect to Control % Reduction — 0 53.10 74.30 72.80 75.2080.50 with respect to Placebo Group I: Untreated Control Group II:Placebo for Acitretin Gel - 0% Group III: Acitretin Gel - 0.02% w/wGroup IV: Acitretin Gel - 0.05% w/w Group V: Acitretin Gel - 0.10% w/wGroup VI: Acitretin Gel - 0.20% w/w Group VII: Reference Test Item -Tazorac ® Gel 0.10% w/w. **Significant at two-sided 1% level ofsignificance; p-value based on Dunnett test for comparing Groups II toVII over Group I (untreated control). @@Significant at two-sided 1%level of significance; p-value based on Dunnett test for comparingGroups III to VII over Group II (placebo for acitretin gel).

Percentage reduction in utricle diameter with respect to control andplacebo has been calculated manually as per given formula and notsubjected to statistical analysis.

As compared to control and placebo, application of acitretin gel at allconcentrations (0.02% w/w, 0.05% w/w, 0.10% w/w, and 0.20% w/w)significantly reduced the utriculi diameter. The percentage reduction inthe utriculi diameter was not much different within different groups,but acitretin gel at and above 0.05% w/w concentration producedcomparable and equivalent effects with that of Tazorac® gel 0.10% w/w.

Gross Pathology Studies

At necropsy, mild to moderate scaling was noticed at the applicationsite in some animals in Group IV (4 of 7 animals), Group V (3 of 7animals), and Group VI (6 of 7 animals). Whereas, in Group VII, 3 of 7animals were found dead and all dead and moribund sacrificed revealedreddish discoloration and scaling of the skin at the application site.Table 8 presents the summary of gross pathology findings.

TABLE 8 Summary of Gross Pathology Findings Group I II III IV V VI VIINo. of Animals 7 7 7 7 7 7 7 No. of Dead 0 0 0 0 0 0 3 External FindingsNAD 7 7 7 3 4 1 0 Scaling at application 0 0 0 4 3 6 1 site(mild/moderate) Reddish discoloration 0 0 0 0 0 0 6 and scaling atapplication site NAD—No Abnormality Detected

Histopathological Studies

Histopathology scores were analyzed by using the Kruskal-Wallis testfollowed by the Wilcoxon-Mann-Whitney test for comparison of medianhistologic scores of Group II to VII with/over untreated control (GroupI) and those of Group III to VII with/over placebo (Group II—Placebo forAcitretin gel). Further, median histology scores for the ventral sideskin (untreated control site) of each group were compared with that ofthe concurrent dorsal side skin (application site) by using the Wilcoxonsigned-rank test. All statistical analyses were performed at 5% level ofsignificance using SAS® Institute's PC SAS 9.1.3.

As compared to untreated control (Group I) and placebo (Group II—placebofor acitretin gel), the severity of dermal inflammation at the site ofthe application (dorsal side skin) revealed was increased in aconcentration-dependent manner as given in Table 9. However, moreanimals treated with Tazorac® gel (Group VII) showed comparativelyhigher dermal inflammation than that of acitretin gel treated animals.

TABLE 9 Summary of Histopathology Findings Group I II III IV V VI VIINo. of Animals 7 7 7 7 7 7 7 No. of Dead 0 0 0 0 0 0 3 Dermal Changes:Inflammation Absent (Grade 0) 6 7 3 1 0 0 1 (85.7)  (100.0) (42.9)(14.3) (0.0) (0.0) (14.3) Minimal (Grade 1) 1 0 3 3 5 3 2 (14.3) (0.0)(42.9) (42.9) (71.4) (42.9) (28.6) Mild (Grade 2) 0 0 1 3 2 3 2 (0.0)(0.0) (14.3) (42.9) (28.6) (42.9) (28.6) Moderate (Grade 3) 0 0 0 0 0 12 (0.0) (0.0) (0.0) (0.0) (0.0) (14.3) (28.6)Figures in parenthesis indicate percent incidence.

1. A stable topical pharmaceutical composition of acitretin comprising atherapeutically effective amount of acitretin, a gelling agent, asolvent, and a co-solvent.
 2. The stable topical pharmaceuticalcomposition of claim 1, wherein the acitretin is present in an amount ofabout 0.02% w/w to about 10% w/w based on total weight of thecomposition.
 3. (canceled)
 4. (canceled)
 5. (canceled)
 6. (canceled) 7.(canceled)
 8. (canceled)
 9. (canceled)
 10. (canceled)
 11. (canceled) 12.(canceled)
 13. (canceled)
 14. (canceled)
 15. (canceled)
 16. (canceled)17. (canceled)
 18. (canceled)
 19. (canceled)
 20. (canceled)
 21. A stabletopical pharmaceutical composition comprising from about 0.02% w/w toabout 0.4% w/w of acitretin based on total weight of the composition,wherein more than about 15% of the acitretin is present in a solubilizedform.
 22. The stable topical pharmaceutical composition of claim 21comprising about 0.02% w/w of acitretin based on total weight of thecomposition, wherein about 100% of the acitretin is present in thesolubilized form.
 23. The stable topical pharmaceutical composition ofclaim 21 comprising about 0.05% w/w of acitretin based on total weightof the composition, wherein about 100% of the acitretin is present inthe solubilized form.
 24. The stable topical pharmaceutical compositionof claim 21 comprising about 0.1% w/w of acitretin based on total weightof the composition, wherein about 70% of the acitretin is present in thesolubilized form.
 25. The stable topical pharmaceutical composition ofclaim 21 comprising about 0.2% w/w of acitretin based on total weight ofthe composition, wherein about 35% of the acitretin is present in thesolubilized form.
 26. The stable topical pharmaceutical composition ofclaim 21, wherein the composition is a gel.
 27. The stable topicalpharmaceutical composition of claim 21, wherein the compositioncomprises a gelling agent, a solvent, and a co-solvent.
 28. The stabletopical pharmaceutical composition of claim 1 or 27, wherein thepercentage of the gelling agent ranges from about 0.05% w/w to about 10%w/w based on total weight of the composition.
 29. The stable topicalpharmaceutical composition of claim 1 or 27, wherein the gelling agentis selected from the group comprising carboxyvinyl polymers, naturalgums, cellulose derivatives, acrylates, alginic acid-propylene glycolester, polyoxyethylene- polyoxypropylene copolymers, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol,silicon dioxide, and mixtures thereof.
 30. The stable topicalpharmaceutical composition of claim 29, wherein the gelling agent is acarboxyvinyl polymer.
 31. The stable topical pharmaceutical compositionof claim 1 or 27, wherein the solvent is selected from the groupcomprising water, white soft paraffin, light liquid paraffin, heavyliquid paraffin, mineral oil, hydrocarbon oil, ester oil, triglycerideoil, oil of plant origin, oil of animal origin, unsaturated orpolyunsaturated oil, essential oil, silicone oil, and mixtures thereof32. The stable topical pharmaceutical composition of claim 31, whereinthe solvent is water.
 33. The stable topical pharmaceutical compositionof claim 1 or 27, wherein the co-solvent is selected from the groupcomprising ethers, glycols, dimethyl isosorbide, fatty acid esters,fatty acids, polyoxyethylene sorbitan esters, and mixtures thereof. 34.The stable topical pharmaceutical composition of claim 33, wherein theco-solvent is diethylene glycol monoethyl ether.
 35. The stable topicalpharmaceutical composition of claim 33, wherein the co-solvent isdimethyl isosorbide.
 36. The stable topical pharmaceutical compositionof claim 33, wherein the co-solvent is polysorbate
 80. 37. The stabletopical pharmaceutical composition of claim 33, wherein the co-solventis a combination of diethylene glycol monoethyl ether, dimethylisosorbide, and polysorbate
 80. 38. The stable topical pharmaceuticalcomposition of claim 37, wherein diethylene glycol monoethyl ether ispresent in a range of about 20% to about 30% w/w based on total weightof the composition.
 39. The stable topical pharmaceutical composition ofclaim 37, wherein dimethyl isosorbide is present in a range of about 1%to about 10% w/w based on total weight of the composition.
 40. Thestable topical pharmaceutical composition of claim 37, whereinpolysorbate 80 is present in a range of about 0.1% to about 5% w/w basedon total weight of the composition.
 41. The stable topicalpharmaceutical composition of claim 1 or 27, wherein the compositionfurther comprises one or more pharmaceutically acceptable excipientsselected from the group comprising percutaneous absorption enhancers,antioxidants, preservatives, chelating agents, surfactants, pH-adjustingagents, humectants, fragrances, and mixtures thereof.
 42. The stabletopical pharmaceutical composition of claim 1 or 27, wherein thecomposition has a pH from about 4 to about
 7. 43. A stable topicalpharmaceutical composition comprising at least about 0.05% w/w ofacitretin based on total weight of the composition, wherein thecomposition has a mean in-vitro release rate of more than about 10.00μg/cm²/h^(1/2) as measured using a Franz diffusion cell with theconditions of receptor solution comprising isopropyl alcohol and water(60:40, v/v), membrane Supor® 200, dosage 300±30 mg, temperature 32°C.±1.0° C.
 44. A method of treating a skin disorder by administering thestable topical pharmaceutical composition of claim 1 or
 21. 45. Themethod of treatment of claim 44, wherein the skin disorder is selectedfrom the group comprising psoriasis, keratosis, eczema, rosacea, acnevulgaris, dermatitis, pruritus, seborrhea, skin cancers, inflammation,other skin disorders which are responsive to acitretin or etretinate,and combinations thereof.
 46. The method of treatment of claim 45,wherein the skin disorder is psoriasis.
 47. A stable topicalpharmaceutical composition effective for treating psoriasis comprisingfrom about 0.05% w/w to about 0.2% w/w of acitretin based on totalweight of the composition, wherein a percentage reduction in utriculisize is comparable to Tazorac® 0.1% gel using a Rhino Mouse Model.
 48. Astable topical pharmaceutical composition effective for treatingpsoriasis comprising from about 0.02% w/w to about 0.2% w/w of acitretinbased on total weight of the composition, wherein the compositionexhibits reduced skin irritancy in comparison to Tazorac® 0.1% gel usinga Rhino Mouse Model.